Expanding the Host Range of Hepatitis C Virus through Viral Adaptation

• DOI: 10.1128/mbio.01915-16
• Publication Date: 2016-11-09T11:00:34Z
• Authors: Markus von Schaewen; Marcus Dorner; Kathrin Hueging; Lander Foquet; Sherif Gerges; Gabriela Hrebikova; Brigitte Heller; Julia Bitzegeio; Juliane Doerrbecker; Joshua A. Horwitz; Gisa Gerold; Sebastian Suerbaum; Charles M. Rice; Philip Meuleman; Thomas Pietschmann; Alexander Ploss
• Keywords: 0301 basic medicine; 570; LIVER; 610; Hepacivirus; Adaptive Immunity; Antibodies, Viral; Microbiology; Host Specificity; Cell Line; Tetraspanin 28; Mice; 03 medical and health sciences; Occludin; INFECTION; Medicine and Health Sciences; Animals; Humans; IDENTIFICATION; RECEPTOR; Biology and Life Sciences; HUMANIZED MICE; Scavenger Receptors, Class B; Virus Internalization; RNA REPLICATION; Adaptation, Physiological; Hepatitis C; LIFE-CYCLE; QR1-502; 3. Good health; Disease Models, Animal; Viral Tropism; MOUSE CELLS; INDEPENDENT MECHANISMS; 13. Climate action; Hepatocytes; ENTRY FACTOR; 0605 Microbiology; Research Article

ABSTRACT Hepatitis C virus (HCV) species tropism is incompletely understood. We have previously shown that at the level of entry, human CD81 and occludin (OCLN) comprise minimal set factors needed for viral uptake into murine cells. As an alternative approach to genetic humanization, barriers can be overcome by adapting HCV use orthologues these entry factors. generated a tropic (mtHCV or Jc1/mCD81) strain harboring three mutations within envelope proteins allowed productive mouse cell lines. In this study, we aimed characterize ability mtHCV enter infect hepatocytes in vivo vitro . Using highly sensitive, Cre-activatable reporter, demonstrate absence any cofactors. Viral still relied on expression SCARB1 was more efficient when OCLN were overexpressed. could significantly reduced presence anti-HCV E2 specific antibodies, suggesting dependent glycoproteins. Despite mtHCV’s , did not observe persistent infection, even animals with severely blunted type I III interferon signaling impaired adaptive immune responses. Altogether, results establish proof concept limiting adaptation. However, additional adaptations will likely increase robustness model system hepatitis C. IMPORTANCE At least 150 million individuals are chronically infected risk developing serious liver disease. advent effective antiviral therapy, frequency chronic carriers has only marginally decreased. A major roadblock vaccine would prevent transmission scarcity animal models susceptible infection. It poorly understood why infects humans chimpanzees. To develop C, previous efforts focused modifying host environment mice, example, render them Here, attempted complementary which laboratory-derived variant tested its mice. engineered cells but does replicate efficiently. Thus, construct robust HCV.